Ca
 2+
 Uptake by the Sarcoplasmic Reticulum in Ventricular Myocytes of the
 SERCA2
 b/b
 Mouse Is Impaired at Higher Ca
 2+
 Loads Only

Antoons, Gudrun; Heyen, Mark Ver; Raeymaekers, Luc; Vangheluwe, Peter; Wuytack, Frank; Sipido, Karin R.

doi:10.1161/01.res.0000069032.81501.98

Cited by 24 publications

(19 citation statements)

References 58 publications

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“…As such an increased mortality was not observed in mice with heterozygous deletion of the SERCA2 gene, the malformation of the embryonic heart appears to be caused by the absence of the SERCA2a isoform rather than the reduced total amount of SERCA2 protein. Mice deficient in SERCA2a that survived to adulthood showed impaired cardiac function and a defect in Ca 2+ uptake, which further points to different roles of SERCA2 isoforms in maintaining these processes (Ver Heyen et al 2001;Antoons et al 2003).…”

Section: Mice With Targeted Disruption Of a Specific Protein Isoformmentioning

confidence: 99%

The impact of alternative splicing in vivo: Mouse models show the way

Möröy

Heyd²

2007

RNA

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Alternative splicing is widely believed to have a major impact on almost all biological processes since it increases proteome complexity and thereby controls protein function. Recently, gene targeting in mice has been used to create in vivo models to study the regulation and consequences of alternative splicing. The evidence accumulated so far argues for a nonredundant, highly specific role of individual splicing factors in mammalian development, and furthermore, demonstrates the importance of distinct protein isoforms in vivo. In this review, we will compare phenotypes of mouse models for alternative splicing to crystallize common themes and to put them into perspective with the available in vitro data.

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Section: Mice With Targeted Disruption Of a Specific Protein Isoformmentioning

confidence: 99%

The impact of alternative splicing in vivo: Mouse models show the way

Möröy

Heyd²

2007

RNA

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“…We observed that in vivo and isolated cardiomyocyte function were only mildly affected in SKO despite a fourfold increase in PLB to SERCA2b (4,28). Using mathematical modeling, we predicted that lower SERCA levels in these mice compensate for the presence of the high Ca 2ϩ affinity SERCA isoform to prevent excessive SR Ca 2ϩ uptake and abnormally low diastolic [Ca 2ϩ ] i (4). When PLB is ablated, SERCA levels are further reduced, which, as indicated by our present findings, maintains Ca 2ϩ cycling in a normal range.…”

Section: Discussionmentioning

confidence: 78%

“…However, it appears that the PLB-to-SERCA ratio may only be a good indicator of contractility and relaxation in a SERCA2a background. We observed that in vivo and isolated cardiomyocyte function were only mildly affected in SKO despite a fourfold increase in PLB to SERCA2b (4,28). Using mathematical modeling, we predicted that lower SERCA levels in these mice compensate for the presence of the high Ca 2ϩ affinity SERCA isoform to prevent excessive SR Ca 2ϩ uptake and abnormally low diastolic [Ca 2ϩ ] i (4).…”

Section: Discussionmentioning

confidence: 95%

“…Ventricular myocytes were enzymatically isolated as described previously (4). Cells were stored at room temperature, and experiments were performed within 6 h of isolation.…”

Section: Methodsmentioning

confidence: 99%

“…SR content was estimated by measuring the magnitude of the caffeine-elicited Ca 2ϩ transient and by integrating the caffeine-induced Na ϩ -Ca 2ϩ -exchange (NCX) current. Elevated Ca 2ϩ loads were induced by blocking Ca 2ϩ extrusion via the Na ϩ -Ca 2ϩ exchanger as described previously (4). The pipette solution in these experiments contained the following (in mmol/l): 120 Cs-aspartate, 10 TEACl, 10 Cs-HEPES, 0.5 MgCl2, 5 MgATP, and 0.05 K5-fluo-3, pH 7.2.…”

Section: Methodsmentioning

confidence: 99%

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Phospholamban ablation in hearts expressing the high affinity SERCA2b isoform normalizes global Ca²⁺ homeostasis but not Ca²⁺-dependent hypertrophic signaling

Louch

Vangheluwe

Bito

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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affinity of SERCA by substituting SERCA2a with the higher affinity SERCA2b pump. When phospholamban was also ablated, these double knockouts (DKO) exhibited a dramatic reduction in total SERCA levels, severe hypertrophy, and diastolic dysfunction. We presently examined the role of cardiomyocyte Ca 2ϩ homeostasis in both functional and structural remodeling in these hearts. Despite the low SERCA levels in DKO, we observed near-normal Ca 2ϩ homeostasis with rapid Ca 2ϩ reuptake even at high Ca 2ϩ loads and stimulation frequencies. Well-preserved global Ca 2ϩ homeostasis in DKO was paradoxically associated with marked activation of the Ca 2ϩ -dependent nuclear factor of activated T-cell-calcineurin pathway known to trigger hypertrophy. No activation of the MAP kinase signaling pathway was detected. These findings suggest that local changes in Ca 2ϩ homeostasis may play an important signaling role in DKO, perhaps due to reduced microdomain Ca 2ϩ buffering by SERCA2b. Furthermore, alterations in global Ca 2ϩ homeostasis can also not explain impaired in vivo diastolic function in DKO. Taken together, our results suggest that normalizing global cardiomyocyte Ca 2ϩ homeostasis does not necessarily protect against hypertrophy and heart failure development and that excessively increasing SERCA Ca 2ϩ affinity may be detrimental. content and cellular contractility. SERCA activity is regulated by phospholamban (PLB), which inhibits SERCA by decreasing its apparent Ca 2ϩ affinity. The pivotal role of PLB as an affinity modulator has been explored in a number of transgenic mouse models. Decreasing the affinity of SERCA for cytosolic

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Factors controlling the activity of the SERCA2a pump in the normal and failing heart

et al. 2009

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Heart failure is the leading cause of death in western countries and is often associated with impaired Ca(2+) handling in the cardiomyocyte. In fact, cardiomyocyte relaxation and contraction are tightly controlled by the activity of the cardiac sarco(endo)plasmic reticulum (ER/SR) Ca(2+) pump SERCA2a, pumping Ca(2+) from the cytosol into the lumen of the ER/SR. This review addresses three important facets that control the SERCA2 activity in the heart. First, we focus on the alternative splicing of the SERCA2 messenger, which is strictly regulated in the developing heart. This splicing controls the formation of three SERCA2 splice variants with different enzymatic properties. Second, we will discuss the role and regulation of SERCA2a activity in the normal and failing heart. The two well-studied Ca(2+) affinity modulators phospholamban and sarcolipin control the activity of SERCA2a within a narrow window. An aberrantly high or low Ca(2+) affinity is often observed in and may even trigger cardiac failure. Correcting SERCA2a activity might therefore constitute a therapeutic approach to improve the contractility of the failing heart. Finally, we address the controversies and unanswered questions of other putative regulators of the cardiac Ca(2+) pump, such as sarcalumenin, HRC, S100A1, Bcl-2, HAX-1, calreticulin, calnexin, ERp57, IRS-1, and -2.

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Ca ²⁺ Uptake by the Sarcoplasmic Reticulum in Ventricular Myocytes of the SERCA2 ^b/b Mouse Is Impaired at Higher Ca ²⁺ Loads Only

Cited by 24 publications

References 58 publications

The impact of alternative splicing in vivo: Mouse models show the way

The impact of alternative splicing in vivo: Mouse models show the way

Phospholamban ablation in hearts expressing the high affinity SERCA2b isoform normalizes global Ca²⁺ homeostasis but not Ca²⁺-dependent hypertrophic signaling

Factors controlling the activity of the SERCA2a pump in the normal and failing heart

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Ca 2+ Uptake by the Sarcoplasmic Reticulum in Ventricular Myocytes of the SERCA2 b/b Mouse Is Impaired at Higher Ca 2+ Loads Only

Cited by 24 publications

References 58 publications

The impact of alternative splicing in vivo: Mouse models show the way

The impact of alternative splicing in vivo: Mouse models show the way

Phospholamban ablation in hearts expressing the high affinity SERCA2b isoform normalizes global Ca2+ homeostasis but not Ca2+-dependent hypertrophic signaling

Factors controlling the activity of the SERCA2a pump in the normal and failing heart

Contact Info

Product

Resources

About

Ca ²⁺ Uptake by the Sarcoplasmic Reticulum in Ventricular Myocytes of the SERCA2 ^b/b Mouse Is Impaired at Higher Ca ²⁺ Loads Only

Phospholamban ablation in hearts expressing the high affinity SERCA2b isoform normalizes global Ca²⁺ homeostasis but not Ca²⁺-dependent hypertrophic signaling